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US5965747A - Crystalline forms of antibiotic side chain intermediates - Google Patents

Crystalline forms of antibiotic side chain intermediates Download PDF

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US5965747A
US5965747A US09/102,449 US10244998A US5965747A US 5965747 A US5965747 A US 5965747A US 10244998 A US10244998 A US 10244998A US 5965747 A US5965747 A US 5965747A
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crystalline
pyrrolidinyl
mercapto
cis
carbonyl
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Karel M. J. Brands
Ronald B. Jobson
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Merck Sharp and Dohme LLC
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Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

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  • Crystalline forms of intermediates for carbapenem antibiotics are desirable from a stability and purity standpoint. These compounds facilitate the synthesis of carbapenem antibiotics on a commercial scale.
  • Crystalline 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]-amino]benzoic acid as well as pharmaceutically acceptable salts and solvates thereof are disclosed.
  • FIG. 1 is an X-Ray Powder Diffraction pattern of Compound I, in unsolvated form
  • FIG. 2 is an X-Ray Powder Diffraction pattern of Compound I as the 1-butanol solvate
  • FIG. 3 is an X-Ray Powder Diffraction pattern of Compound I, as the acetic acid solvate.
  • the compound has the following structural formula: ##STR1## wherein P represents H or a protecting group.
  • the salt form of the compound can be protonated as shown in the following: ##STR2## wherein X - represents a negatively charged counterion.
  • the salt forms can also be present in the form of a solvate.
  • the crystalline forms of the compound are characterized below by virtue of their X-Ray Powder Diffraction (XRPD) patterns.
  • XRPD X-Ray Powder Diffraction
  • the XRPD patterns were collected on a Philips APD 3720 automated powder diffractometer.
  • the x-ray generator employed a copper target, an accelerating potential of 45 kV and a filament emission of 40 mA. Diffraction patterns were collected from 2° C. to 40° C.
  • the hydrochloride salt of the compound was characterized as having an XRPD pattern at 5.5, 5.3, 4.9, 4.3, 4.1, 3.9, 3.8, 3.7, 3.6, 3.3, 3.2, 2.9, 2.6 and 2.3 angstroms. More complete XRPD data pertaining to the compound is shown below in Table 1.
  • the XRPD pattern corresponding to Table I is shown as FIG. 1.
  • the hydrochloride salt 1-butanol solvate was shown to exhibit patterns such as the ERPD pattern shown as FIG. 2. Characteristic D-spacings are 14.6, 7.3, 5.6, 4.9, 4.2, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.3, 3.0 and 2.9 Ang. More complete XRPD data pertaining to the solvate is shown below in Table 2.
  • the XRPD pattern corresponding to Table 2 is shown as FIG. 2.
  • Solid material which was exposed to acetic acid was characterized as having an XRPD pattern at 5.4, 5.3, 5.1, 4.2, 3.8, 3.6, 3.4, 3.1, 2.7 and 2.6 angstroms. More complete XRPD data pertaining to the solvate is shown below in Table 3.
  • the XRPD pattern corresponding to Table 3 is shown as FIG. 3.
  • the crystalline compound of the present invention is useful in various pharmaceutically acceptable salt forms, for the synthesis of carbapenem compounds that are in turn useful for the treatment of bacterial infections in animal and human subjects.
  • pharmaceutically acceptable salt refers to those salt forms which would be apparent to the pharmaceutical chemist. i.e., those which are substantially non-toxic and which provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion.
  • Other factors, more practical in nature, which are also important in the selection, are cost of the raw materials, ease of crystallization, yield, stability, hygroscopicity and flowability of the resulting bulk drug.
  • the intermediate compound is protonated, and is found in association with a negatively charged counterion, represented by the generic X - .
  • a negatively charged counterion represented by the generic X - .
  • charge balancing counterion X - there are various possibilities for the charge balancing counterion X - .
  • Representative examples of such counterions are the following: acetate, adipate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, benzoate, benzenesulfonate, bicarbonate, bisulfate, bromide, citrate, camphorate, camphorsulfonate, carbonate, chloride, digluconate, edetate, edisylate, estolate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycolate, hydroxynaphthoate, 2-hydroxyethan
  • the preferred form of the crystalline compound is the hydrochloride salt form.
  • the compound can be produced in accordance with the following non-limiting examples.
  • the BOC protected sidechain 1 (prepared according to the teachings of PCT WO97/06154 published on Feb. 20, 1997) was dissolved in 1.5 L of a 1 N solution of dry hydrogen chloride in acetic acid (30 min). Gas evolution was observed and the reaction product slowly crystallized. After filtering, washing (with acetic acid and hexane) and drying 137 g of product was obtained. The crystals contain acetic acid but are not a solvate.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Crystalline 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl) carbonyl]-amino]benzoic acid and salts and solvates thereof are disclosed. Three different crystalline types are described.

Description

RELATED APPLICATION
This application claims the benefit of Ser. No. 60/052,197 filed on Jul. 10, 1997.
BACKGROUND OF THE INVENTION
Crystalline forms of intermediates for carbapenem antibiotics are desirable from a stability and purity standpoint. These compounds facilitate the synthesis of carbapenem antibiotics on a commercial scale.
In the present invention, crystalline forms of the compound 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]-amino]benzoic acid have been discovered and characterized. Crystalline 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]-amino]benzoic acid and pharmaceutically acceptable salts and solvates thereof are disclosed. The compounds can generally be synthesized taking into account the disclosure of U.S. Pat. No. 5,478,820 granted on Dec. 26, 1995. This patent does not disclose the side chain in crystalline form.
SUMMARY OF THE INVENTION
Crystalline 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]-amino]benzoic acid as well as pharmaceutically acceptable salts and solvates thereof are disclosed.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention is described in connection with the following drawings, of which:
FIG. 1 is an X-Ray Powder Diffraction pattern of Compound I, in unsolvated form;
FIG. 2 is an X-Ray Powder Diffraction pattern of Compound I as the 1-butanol solvate, and FIG. 3 is an X-Ray Powder Diffraction pattern of Compound I, as the acetic acid solvate.
DETAILED DESCRIPTION OF THE INVENTION
The compound has the following structural formula: ##STR1## wherein P represents H or a protecting group.
The salt form of the compound can be protonated as shown in the following: ##STR2## wherein X- represents a negatively charged counterion. The salt forms can also be present in the form of a solvate.
The crystalline forms of the compound are characterized below by virtue of their X-Ray Powder Diffraction (XRPD) patterns. The XRPD patterns were collected on a Philips APD 3720 automated powder diffractometer. The x-ray generator employed a copper target, an accelerating potential of 45 kV and a filament emission of 40 mA. Diffraction patterns were collected from 2° C. to 40° C.
The hydrochloride salt of the compound (unsolvated material) was characterized as having an XRPD pattern at 5.5, 5.3, 4.9, 4.3, 4.1, 3.9, 3.8, 3.7, 3.6, 3.3, 3.2, 2.9, 2.6 and 2.3 angstroms. More complete XRPD data pertaining to the compound is shown below in Table 1.
                                  TABLE 1                                 
__________________________________________________________________________
       Tip                                                                
  Peak Angle Width Peak Backg D Spac I/Imax Type                          
No.                                                                       
   (deg)                                                                  
       (deg)                                                              
           (cts)                                                          
               (cts)                                                      
                   (Ang)                                                  
                        (%) A1 A2                                         
                                 Ot Sign                                  
__________________________________________________________________________
 1 8.3325                                                                 
       0.48                                                               
           10. 6.  10.6028                                                
                        2.34                                              
                            x  x    0.83                                  
   2 9.7600 0.12 19. 7. 9.0550 4.43 x x  0.89                             
   3 12.1375 0.36 10. 8. 7.2861 2.34 x x  1.05                            
   4 14.1525 0.15 17. 9. 6.2529 3.85 x x  0.91                            
   5 16.1575 0.15 46. 12. 5.4812 10.59 x x  2.09                          
   6 16.6450 0.15 53. 12. 5.3218 12.20 x x  1.02                          
   7 16.8200 0.15 41. 12. 5.2668 9.38 x x  0.91                           
   8 17.6250 0.24 30. 13. 5.0280 6.93 x x  1.26                           
   9 18.2600 0.07 154. 13. 4.8546 35.20 x x  1.38                         
  10 18.9025 0.18 17. 14. 4.6910 3.85 x x  1.26                           
  11 19.5625 0.12 34. 14. 4.5342 7.70 x x  0.76                           
  12 20.5175 0.09 117. 15 4.3252 26.70 x x  1.07                          
  13 21.6225 0.21 48. 16 4.1066 10.90 x x  2.88                           
  14 22.6875 0.13 437. 17 3.9162 100.00 x x  5.62                         
  15 23.4200 0.09 12&. 18 3.7954 29.23 x x  0.78                          
  16 23.8750 0.18 96. 18 3.7241 21.99 x x  3.47                           
  17 24.4900 0.12 72. 18 3.6319 16.54 x x  3.02                           
  18 25.0125 0.18 26. 18 3.5572 5.95 x x  0.89                            
  19 25.7275 0.18 20. 19 3.4599 4.64 x x  0.83                            
  20 26.6250 0.18 114. 20 3.3453 26.21 x x  2.09                          
  21 26.9725 0.09 246. 20 3.3030 56.43 x x  1.74                          
  22 27.9675 0.07 202. 21 3.1877 46.16 x x  1.32                          
  23 28.5925 0.24 30. 22 3.1194 6.93 x x  1.05                            
  24 30.8400 0.07 196. 24 2.8970 44.87 x x  1.55                          
  25 32.1275 0.18 38. 24 2.7838 8.80 x x  1.82                            
  26 32.6325 0.18 58. 25 2.7419 13.22 x x  2.04                           
  27 33.9250 0.18 174. 26 2.6403 39.89 x x  5.13                          
  28 35.1000 0.18 17. 27 2.5546 3.85 x x  1.05                            
  29 35.7950 0.24 32. 27 2.5065 7.44 x x  3.16                            
  30 36.8400 0.36 37. 28 2.4378 8.52 x x  2.45                            
  31 37.3975 0.15 35. 28 2.4027 7.97 x x  1.07                            
  32 37.8050 0.15 35. 28 2.3778 7.97 x x  1.15                            
  33 38.5300 0.12 69. 29 2.3347 15.77 x x  1.15                           
__________________________________________________________________________
 Notes:                                                                   
 Generator settings: 45kV, 40 mA                                          
 Cu alpha1, 2 wave lengths 1.54060, 1.54439 Ang                           
 Step size, sample time 0.015 deg, 0.20 s, 0.075 deg/s                    
 Monochromator used                                                       
 Divergence slit Automatic (irradiated sample length 12.5 mm)             
 Peak angle range 2.007-40.002 deg                                        
 Range in D spacing 2.25207-43.9723 Ang                                   
 Peak position criterion Top of smoothed data                             
 Cryst peak width range 0.00-2.00 deg                                     
 Minim peak significance 0.75                                             
 Number of peaks in file 33 (alpha1: 33, amorphous: 0)                    
 Maximum intensity 437. cts, 2184. 1 cps
The XRPD pattern corresponding to Table I is shown as FIG. 1.
The hydrochloride salt 1-butanol solvate was shown to exhibit patterns such as the ERPD pattern shown as FIG. 2. Characteristic D-spacings are 14.6, 7.3, 5.6, 4.9, 4.2, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.3, 3.0 and 2.9 Ang. More complete XRPD data pertaining to the solvate is shown below in Table 2.
                                  TABLE 2                                 
__________________________________________________________________________
       Tip                                                                
  Peak Angle Width Peak Backg D Spac I/Imax Type                          
No.                                                                       
   (deg)                                                                  
       (deg)                                                              
           (cts)                                                          
               (cts)                                                      
                   (Ang)                                                  
                        (%) A1 A2                                         
                                 Ot Sign                                  
__________________________________________________________________________
 1 3.0625                                                                 
       0.72                                                               
           10  0.  28.8263                                                
                        1.84                                              
                            x  x    1.20                                  
   2 6.0675 0.07 557 4. 14.5548 100.00 x x  5.75                          
   3 9.7950 0.18 10. 5. 9.0227 1.84 x x  0.85                             
   4 11.1825 0.15 14. 6. 7.9061 2.59 x x  1.10                            
   5 12.0625 0.09 135. 6. 7.3312 24.16 x x  3.09                          
   6 12.8450 0.12 19. 7. 6.8863 3.48 x x  1.12                            
   7 15.8225 0.07 62. 8. 5.5965 11.21 x x  1.35                           
   8 16.7900 0.30 12. 10. 5.2761 2.08 x x  0.95                           
   9 17.9150 0.07 98. 10. 4.9473 17.60 x x  1.17                          
  10 18.2525 0.21 119. 11. 4.8566 21.33 x x  6.46                         
  11 18.7050 0.09 30. 11. 4.7401 5.43 x x  1.29                           
  12 20.5575 0.09 31. 13. 4.3169 5.63 x x  1.32                           
  13 21.3925 0.12 376. 13. 4.1503 67.57 x x  7.08                         
  14 21.9375 0.06 159. 14. 4.0484 28.50 x x  0.81                         
  15 22.3975 0.12 144. 14. 3.9663 25.85 x x  4.07                         
  16 22.7650 0.06 132. 15. 3.9031 23.74 x x  1.23                         
  17 23.5475 0.07 114. 16. 3.7751 20.56 x x  1.10                         
  18 24.2675 0.06 180. 17. 3.6647 32.24 x x  1.02                         
  19 24.8675 0.09 149. 17. 3.5776 26.72 x x  2.04                         
  20 25.1500 0.06 98. 18. 3.5381 17.60 x x  0.79                          
  21 25.8000 0.07 108. 18. 3.4504 19.42 x x  1.35                         
  22 26.7525 0.12 159. 18. 3.3297 28.50 x x  1.17                         
  23 27.3775 0.07 77. 19. 3.2551 13.90 x x  0.93                          
  24 28.0575 0.15 37. 20. 3.1777 6.68 x x  1.51                           
  25 29.0475 0.15 45. 20. 3.0716 8.06 x x  1.41                           
  26 29.5925 0.10 142. 21. 3.0163 25.43 x x  2.63                         
  27 30.0575 0.06 117. 22. 2.9706 20.94 x x  0.78                         
  28 30.3500 0.12 58. 22. 2.9427 10.37 x x  0.93                          
  29 30.7375 0.24 117. 23. 2.9065 20.94 x x  7.76                         
  30 31.3225 0.18 30. 23. 2.8535 5.43 x x  1.38                           
  31 32.0950 0.12 35. 24. 2.7866 6.25 x x.  0.87                          
  32 32.8725 0.18 25. 24. 2.7224 4.49 x x  1.07                           
  33 33.4025 0.24 18. 25. 2.6804 3.32 x x  0.85                           
  34 33.9575 0.24 76. 26. 2.6379 13.59 x x  4.37                          
  35 34.5225 0.04 42. 26. 2.5960 7.59 x x  0.76                           
  36 34.9325 0.06 37. 27. 2.5664 6.68 x x  0.78                           
  37 35.4450 0.09 67. 27. 2.5305 12.07 x x  1.45                          
  38 36.2300 0.21 36. 28. 2.4774 6.46 x x  2.88                           
  39 37.3500 0.12 49. 29. 2.4057 8.80 x x  1.38                           
  40 38.2150 0.12 52. 29. 2.3532 9.31 x x  1.20                           
__________________________________________________________________________
 Notes:                                                                   
 Generator settings: 45kV, 40 mA                                          
 Cu alpha1, 2 wavelengths 1.54060, 1.54439 Ang                            
 Step size, sample time 0.015 deg, 0.20 s, 0.075 deg/s                    
 Monochromator used                                                       
 Divergence slit Automatic (irradiated sample length 12.5 mm)             
 Peak angle range 2.007-40.002 deg                                        
 Range in D spacing 2.25207-43.9723 Ang                                   
 Peak position criterion Top of smoothed data                             
 Cryst peak width range 0.00-2.00 deg                                     
 Minim peak significance 0.75                                             
 Number of peaks in file 33 (alpha1: 33, amorphous: 0)                    
 Maximum intensity 437. cts, 2184. 1 cps
The XRPD pattern corresponding to Table 2 is shown as FIG. 2.
Solid material which was exposed to acetic acid was characterized as having an XRPD pattern at 5.4, 5.3, 5.1, 4.2, 3.8, 3.6, 3.4, 3.1, 2.7 and 2.6 angstroms. More complete XRPD data pertaining to the solvate is shown below in Table 3.
                                  TABLE 3                                 
__________________________________________________________________________
       Tip                                                                
  Peak Angle Width Peak Backg D Spac I/Imax Type                          
No.                                                                       
   (deg)                                                                  
       (deg)                                                              
           (cts)                                                          
               (cts)                                                      
                   (Ang)                                                  
                        (%) A1 A2                                         
                                 Ot Sign                                  
__________________________________________________________________________
 1 3.1400                                                                 
       0.96                                                               
           10. -1. 28.1149                                                
                        2.96                                              
                            x  x    0.81                                  
   2 6.0350 0.24 12. 5. 14.6331 3.34 x x  0.95                            
   3 11.4925 0.12 32. 10. 7.6935 9.39 x x  0.95                           
   4 11.9925 0.24 48. 10. 7.3739 13.76 x x  4.47                          
   5 12.8950 0.18 17. 10. 6.8597 4.86 x x  1.00                           
   6 16.3050 0.21 202. 12. 5.4320 58.28 x x  7.76                         
   7 16.6950 0.09 86. 13. 5.3060 25.00 x x  1.02                          
   8 17.5350 0.07 130. 13. 5.0536 37.57 x x  0.95                         
   9 18.0250 0.09 38. 14. 4.9173 11.11 x x  0.98                          
  10 20.0125 0.24 37. 16. 4.4332 10.76 x x  1.70                          
  11 20.4650 0.09 56. 16. 4.3362 16.26 x x  1.12                          
  12 21.0225 0.10 149. 17. 4.2225 43.02 x x  1.95                         
  13 21.8425 0.06 81. 18. 4.0658 23.41 x x  0.85                          
  14 23.2675 0.33 346. 19. 3.8199 100.00 x x  21.88                       
  15 23.9075 0.30 77. 19. 3.7191 22.38 x x  1.58                          
  16 24.8525 0.09 216. 21. 3.5797 62.46 x x  1.02                         
  17 25.9625 0.30 213. 22. 3.4292 61.61 x x  12.02                        
  18 26.5600 0.30 110. 23. 3.3534 31.87 x x  2.45                         
  19 27.3000 0.18 48. 23. 3.2641 13.76 x x  0.79                          
  20 27.4900 0.36 42. 23. 3.2420 12.21 x x  0.85                          
  21 28.2425 0.18 29. 24. 3.1573 8.43 x x  0.76                           
  22 28.9025 0.09 62. 25. 3.0867 18.04 x x  1.07                          
  23 29.7375 0.18 38. 26. 3.0019 11.11 x x  1.17                          
  24 30.3075 0.15 28. 26. 2.9467 8.12 x x  1.00                           
  25 31.2550 0.18 32. 27. 2.8595 9.39 x x  0.78                           
  26 32.9850 0.30 83. 29. 2.7134 23.94 x x  3.24                          
  27 33.3150 0.18 62. 29. 2.6872 18.04 x x  0.81                          
  28 33.9350 0.09 48. 30. 2.6396 13.76 x x  1.02                          
  29 34.4175 0.15 74. 30. 2.6036 21.38 x x  1.91                          
  30 35.0900 0.36 42. 31. 2.5553 12.21 x x  2.40                          
  31 35.9900 0.36 40. 32. 2.4934 11.47 x x  2.14                          
  32 37.0675 0.30 62. 34. 2.4234 18.04 x x  1.78                          
  33 38.4225 0.24 41. 35. 2.3410 11.84 x x  0.95                          
__________________________________________________________________________
 Notes:                                                                   
 Generator settings: 45kV, 40 mA                                          
 Cu alpha1, 2 wavelengths 1.54060, 1.54439 Ang                            
 Step size, sample time 0.015 deg, 0.20 s, 0.075 deg/s                    
 Monochromator used                                                       
 Divergence slit Automatic (irradiated sample length 12.5 mm)             
 Peak angle range 2.007-40.002 deg                                        
 Range in D spacing 2.25207-43.9723 Ang                                   
 Peak position criterion Top of smoothed data                             
 Cryst peak width range 0.00-2.00 deg                                     
 Minim peak significance 0.75                                             
 Number of peaks in file 33 (alpha1: 33, amorphous: 0)                    
 Maximum intensity 437. cts, 2184.1 cps
The XRPD pattern corresponding to Table 3 is shown as FIG. 3.
The crystalline compound of the present invention is useful in various pharmaceutically acceptable salt forms, for the synthesis of carbapenem compounds that are in turn useful for the treatment of bacterial infections in animal and human subjects. The term "pharmaceutically acceptable salt" refers to those salt forms which would be apparent to the pharmaceutical chemist. i.e., those which are substantially non-toxic and which provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion. Other factors, more practical in nature, which are also important in the selection, are cost of the raw materials, ease of crystallization, yield, stability, hygroscopicity and flowability of the resulting bulk drug.
Typically the intermediate compound is protonated, and is found in association with a negatively charged counterion, represented by the generic X-. There are various possibilities for the charge balancing counterion X-. Representative examples of such counterions are the following: acetate, adipate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, benzoate, benzenesulfonate, bicarbonate, bisulfate, bromide, citrate, camphorate, camphorsulfonate, carbonate, chloride, digluconate, edetate, edisylate, estolate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycolate, hydroxynaphthoate, 2-hydroxyethanesulfonate, iodide, lactate, lactobionate, malate, maleate, mandelate, methylenebis(salicylate), mucate, methanesulfonate, napadisylate, napsylate, pamoate, pantothenate, pectinate, phosphate/diphosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfate, tartrate, triflate, tosylate and undecanoate. Other anionic species will be apparent to the ordinarily skilled chemist.
The preferred form of the crystalline compound is the hydrochloride salt form.
The compound can be produced in accordance with the following non-limiting examples.
EXAMPLE ONE ##STR3##
The BOC protected sidechain 1 (prepared according to the teachings of PCT WO97/06154 published on Feb. 20, 1997) was dissolved in 1.5 L of a 1 N solution of dry hydrogen chloride in acetic acid (30 min). Gas evolution was observed and the reaction product slowly crystallized. After filtering, washing (with acetic acid and hexane) and drying 137 g of product was obtained. The crystals contain acetic acid but are not a solvate.
B. Recrystallization Procedures
1-Propanol Solvate
The above product (25 g) was dissolved in 1-propanol (500 mL) at 100° C. Upon cooling the product crystallized out. After filtering, washing (with 1-propanol and hexane) and drying 20 g of the 1-propanol solvate was obtained.
1-Butanol Solvate
The above product (25 g) was dissolved in a mixture of 1-butanol (225 mL) and water (25 mL) at RT. The resulting solution was concentrated in vacuo to a total volume of 125 mL and seeded with authentic 1-butanol solvate. The crystals were filtered, washed (with 1-butanol and hexane) and dried at RT to give 25 g of the 1-butanol solvate.
Acetic Acid Solvate
The above product was slurried overnight in a 95/5 mixture of acetic acid and water at RT and then partially concentrated via distillation in vacuo. The crystals were filtered, washed (with acetic acid and hexane) and dried to give the acetic acid solvate.

Claims (7)

What is claimed is:
1. Crystalline 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]amino]benzoic acid or a pharmaceutically acceptable salt or solvate thereof.
2. Crystalline 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]amino]benzoic acid in accordance with claim 1, having an X-ray powder diffraction pattern in accordance with FIG. 1, 2 or 3.
3. Crystalline 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]amino]benzoic acid in accordance with claim 1 as the hydrochloride salt.
4. Crystalline 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]amino]benzoic acid in accordance with claim 3 as the hydrochloride salt unsolvated form.
5. Crystalline 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]amino]benzoic acid in accordance with claim 3 as the hydrochloride salt 1-butanol solvate.
6. Crystalline 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]amino]benzoic acid in accordance with claim 3 as the hydrochloride salt acetic acid solvate.
7. Crystalline 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]amino]benzoic acid in accordance with claim 1, having one of the following X-ray powder diffraction patterns:
              TABLE                                                       
______________________________________                                    
d - Spacings (Å) - HCl salt                                           
  Unsolvated    1-butanol solvate                                         
                            Acetic acid solvate                           
______________________________________                                    
5.5         14.6        5.4                                               
  5.3 7.3 5.3                                                             
  4.9 5.6 5.1                                                             
  4.3 4.9 4.2                                                             
  4.1 4.2 3.8                                                             
  3.9 4.0 3.6                                                             
  3.8 3.9 3.4                                                             
  3.7 3.8 3.1                                                             
  3.6 3.7 2.7                                                             
  3.3 3.6 2.6                                                             
  3.2 3.5                                                                 
  2.9 3.3                                                                 
  2.6 3.0                                                                 
  2.3 2.9                                                                 
______________________________________
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001064636A1 (en) * 2000-03-01 2001-09-07 Merck & Co., Inc. Crystalline forms of antibiotic side chain intermediates
US20030045484A1 (en) * 2000-12-18 2003-03-06 Dennis Keith Methods for preparing purified daptomycin
US20040235817A1 (en) * 2001-09-26 2004-11-25 Brands Karel M. J. Crystalline forms of ertapenem sodium
US20090197799A1 (en) * 2000-12-18 2009-08-06 Dennis Keith Methods for preparing purified lipotides

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5478820A (en) * 1992-02-04 1995-12-26 Zeneca Ltd. Antibiotic compounds
WO1997006154A1 (en) * 1995-08-04 1997-02-20 Merck & Co., Inc. Process for synthesizing carbapenem side chain intermediates

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5478820A (en) * 1992-02-04 1995-12-26 Zeneca Ltd. Antibiotic compounds
WO1997006154A1 (en) * 1995-08-04 1997-02-20 Merck & Co., Inc. Process for synthesizing carbapenem side chain intermediates

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1261584A4 (en) * 2000-03-01 2003-06-18 Merck & Co Inc Crystalline forms of antibiotic side chain intermediates
US6479667B2 (en) 2000-03-01 2002-11-12 Merck & Co., Inc. Crystalline forms of antibiotic side chain intermediates
EP1261584A1 (en) * 2000-03-01 2002-12-04 Merck & Co., Inc. Crystalline forms of antibiotic side chain intermediates
WO2001064636A1 (en) * 2000-03-01 2001-09-07 Merck & Co., Inc. Crystalline forms of antibiotic side chain intermediates
US20100041589A2 (en) * 2000-12-18 2010-02-18 Dennis Keith Methods for preparing purified lipopeptides
US20090197799A1 (en) * 2000-12-18 2009-08-06 Dennis Keith Methods for preparing purified lipotides
US20030045484A1 (en) * 2000-12-18 2003-03-06 Dennis Keith Methods for preparing purified daptomycin
US8697638B2 (en) 2000-12-18 2014-04-15 Cubist Pharmaceuticals, Inc. Methods for preparing purified lipopeptides
US8796224B2 (en) 2000-12-18 2014-08-05 Cubist Pharmaceuticals, Inc. Methods for preparing purified lipopeptides
US8846610B2 (en) 2000-12-18 2014-09-30 Cubist Pharmaceuticals, Inc. Methods for preparing purified lipopeptides
US20040235817A1 (en) * 2001-09-26 2004-11-25 Brands Karel M. J. Crystalline forms of ertapenem sodium
US7145002B2 (en) 2001-09-26 2006-12-05 Merck & Co. Inc. Crystalline forms of carbapenem antibiotics and methods of preparation
USRE40794E1 (en) 2001-09-26 2009-06-23 Merck & Co., Inc. Crystalline forms of carbapenem antibiotics and methods of preparation

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